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The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) for temporary mechanical circulatory support in various clinical scenarios has been increasing consistently, despite the lack of sufficient evidence regarding its benefit and safety from adequately powered randomized controlled trials. Although the ARREST trial (Advanced Reperfusion Strategies for Patients with Out-of-Hospital Cardiac Arrest and Refractory Ventricular Fibrillation) and a secondary analysis of the PRAGUE OHCA trial (Prague Out-of-Hospital Cardiac Arrest) provided some evidence in favor of VA-ECMO in the setting of out-of-hospital cardiac arrest, the INCEPTION trial (Early Initiation of Extracorporeal Life Support in Refractory Out-of-Hospital Cardiac Arrest) has not found a relevant improvement of short-term mortality with extracorporeal cardiopulmonary resuscitation. In addition, the results of the recently published ECLS-SHOCK trial (Extracorporeal Life Support in Cardiogenic Shock) and ECMO-CS trial (Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock) discourage the routine use of VA-ECMO in patients with infarct-related cardiogenic shock. Ongoing clinical trials (ANCHOR [Assessment of ECMO in Acute Myocardial Infarction Cardiogenic Shock, NCT04184635], REVERSE [Impella CP With VA ECMO for Cardiogenic Shock, NCT03431467], UNLOAD ECMO [Left Ventricular Unloading to Improve Outcome in Cardiogenic Shock Patients on VA-ECMO, NCT05577195], PIONEER [Hemodynamic Support With ECMO and IABP in Elective Complex High-risk PCI, NCT04045873]) may clarify the usefulness of VA-ECMO in specific patient subpopulations and the efficacy of combined mechanical circulatory support strategies. Pending further data to refine patient selection and management recommendations for VA-ECMO, it remains uncertain whether the present usage of this device improves outcomes.
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Oxigenação por Membrana Extracorpórea , Infarto do Miocárdio , Parada Cardíaca Extra-Hospitalar , Intervenção Coronária Percutânea , Humanos , Oxigenação por Membrana Extracorpórea/métodos , Infarto do Miocárdio/etiologia , Parada Cardíaca Extra-Hospitalar/terapia , Parada Cardíaca Extra-Hospitalar/etiologia , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/terapia , Ensaios Clínicos como AssuntoRESUMO
Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.
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Antígenos de Diferenciação de Linfócitos B , Linfócitos T CD4-Positivos , COVID-19 , Antígenos de Histocompatibilidade Classe II , Oxirredutases Intramoleculares , Ativação Linfocitária , Fatores Inibidores da Migração de Macrófagos , SARS-CoV-2 , Humanos , Antígenos de Diferenciação de Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Ativação Linfocitária/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Movimento Celular , Masculino , Feminino , Pessoa de Meia-Idade , Receptores ImunológicosRESUMO
Dysregulation of the myeloid cell compartment is a feature of severe disease in hospitalized COVID-19 patients. Here, we investigated the response of circulating dendritic cell (DC) and monocyte subpopulations in SARS-CoV-2 infected outpatients with mild disease and compared it to the response of healthy individuals to yellow fever vaccine virus YF17D as a model of a well-coordinated response to viral infection. In SARS-CoV-2-infected outpatients circulating DCs were persistently reduced for several weeks whereas after YF17D vaccination DC numbers were decreased temporarily and rapidly replenished by increased proliferation until 14 days after vaccination. The majority of COVID-19 outpatients showed high expression of CD86 and PD-L1 in monocytes and DCs early on, resembling the dynamic after YF17D vaccination. In a subgroup of patients, low CD86 and high PD-L1 expression were detected in monocytes and DCs coinciding with symptoms, higher age, and lower lymphocyte counts. This phenotype was similar to that observed in severely ill COVID-19 patients, but less pronounced. Thus, prolonged reduction and dysregulated activation of blood DCs and monocytes were seen in a subgroup of symptomatic non-hospitalized COVID-19 patients while a transient coordinated activation was characteristic for the majority of patients with mild COVID-19 and the response to YF17D vaccination.
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COVID-19 , Febre Amarela , Humanos , Monócitos , Antígeno B7-H1/metabolismo , SARS-CoV-2 , Vírus da Febre Amarela , Vacinação , Células DendríticasRESUMO
In the early phase of the COVID-19 pandemic, many local collections of clinical data on patients infected with SARS-CoV-2 were initiated in Germany. As part of the National Pandemic Cohort Network (NAPKON) of the University Medicine Network, the "Integration Core" was established to design the legal, technical and organisational requirements for the integration of inventory data into ongoing prospective data collections and to test the feasibility of the newly developed solutions using use cases (UCs). Detailed study documents of the data collections were obtained. After structured document analysis, a review board evaluated the integrability of the data in NAPKON according to defined criteria. Of 30 university hospitals contacted, 20 responded to the request. Patient information and consent showed a heterogeneous picture with regard to the pseudonymised transfer of data to third parties and re-contact. The majority of the data collections (n=13) met the criteria for integration into NAPKON; four studies would require adjustments to the regulatory documents. Three cohorts were not suitable for inclusion in NAPKON. The legal framework for retrospective data integration and consent-free data use via research clauses (§27 BDSG) was elaborated by a legal opinion by TMF - Technology, Methods and Infrastructure for Networked Medical Research, Berlin. Two UCs selected by the NAPKON steering committee (CORKUM, LMU Munich; Pa-COVID-19, Charité- Universitätsmedizin Berlin) were used to demonstrate the feasibility of data integration in NAPKON by the end of 2021. Quality assurance and performance-based reimbursement of the cases were carried out according to the specifications. Based on the results, recommendations can be formulated for various contexts in order to create technical-operational prerequisites such as interoperability, interfaces and data models for data integration and to fulfil regulatory requirements on ethics, data protection, medical confidentiality and data access when integrating existing cohort data. The possible integration of data into research networks and their secondary use should be taken into account as early as the planning phase of a study - particularly with regard to informed consent - in order to maximise the benefits of the data collected.
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The Impella device (Impella, Abiomed, Danvers, MA) is a percutaneous transvalvular microaxial flow pump that is currently used for (1) cardiogenic shock, (2) left ventricular unloading (combination of venoarterial extracorporeal membrane oxygenation and Impella concept), (3) high-risk percutaneous coronary interventions, (4) ablation of ventricular tachycardia, and (5) treatment of right ventricular failure. Impella-assisted forward blood flow increased mean arterial pressure and cardiac output, peripheral tissue perfusion, and coronary blood flow in observational studies and some randomized trials. However, because of the need for large-bore femoral access (14 F for the commonly used Impella CP device) and anticoagulation, the incidences of bleeding and ischemic complications are as much as 44% and 18%, respectively. Hemolysis is reported in as many as 32% of patients and stroke in as many as 13%. Despite the rapidly growing use of the Impella device, there are still insufficient data on its effect on outcome and complications on the basis of large, adequately powered randomized controlled trials. The only 2 small and also underpowered randomized controlled trials in cardiogenic shock comparing Impella versus intra-aortic balloon pump did not show improved mortality. Several larger randomized controlled trials are currently recruiting patients or are in preparation in cardiogenic shock (DanGer Shock [Danish-German Cardiogenic Shock Trial; NCT01633502]), left ventricular unloading (DTU-STEMI [Door-To-Unload in ST-Segment-Elevation Myocardial Infarction; NCT03947619], UNLOAD ECMO [Left Ventricular Unloading to Improve Outcome in Cardiogenic Shock Patients on VA-ECMO], and REVERSE [A Prospective Randomised Trial of Early LV Venting Using Impella CP for Recovery in Patients With Cardiogenic Shock Managed With VA ECMO; NCT03431467]) and high-risk percutaneous coronary intervention (PROTECT IV [Impella-Supported PCI in High-Risk Patients With Complex Coronary Artery Disease and Reduced Left Ventricular Function; NCT04763200]).
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Cardiologia , Oxigenação por Membrana Extracorpórea , Coração Auxiliar , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Oxigenação por Membrana Extracorpórea/efeitos adversos , Coração Auxiliar/efeitos adversos , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Choque Cardiogênico , Resultado do TratamentoRESUMO
Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.
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COVID-19/imunologia , Células Dendríticas/imunologia , Regeneração/imunologia , SARS-CoV-2/imunologia , Adulto , Antígenos CD/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , COVID-19/patologia , Células Dendríticas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Receptor de Morte Celular Programada 1/imunologiaRESUMO
PURPOSE: Lung transplant recipients are at increased risk of severe disease following infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) due to high-dose immunosuppressive drugs and the lung is the main organ affected by Coronavirus disease 2019 (COVID-19). Several studies have confirmed increased SARS-CoV-2-related mortality and morbidity in patients living with lung allografts; however, detailed immunological studies of patients with SARS-CoV-2 infection in the early phase following transplantation remain scarce. METHODS: We investigated patients who were infected with SARS-CoV-2 in the early phase (18-103 days) after receiving double-lung allografts (n = 4, LuTx) in comparison to immunocompetent patients who had not received solid organ transplants (n = 88, noTx). We analyzed SARS-CoV-2-specific antibody responses against the SARS-CoV-2 spike and nucleocapsid proteins using enzyme-linked immunosorbent assays (ELISA), chemiluminescence immunoassays (CLIA), and immunoblot assays. T cell responses were investigated using Elispot assays. RESULTS: One LuTx patient suffered from persistent infection with fatal outcome 122 days post-infection despite multiple interventions including remdesivir, convalescent plasma, and the monoclonal antibody bamlanivimab. Two patients experienced clinically mild disease with prolonged viral shedding (47 and 79 days), and one patient remained asymptomatic. Antibody and T cell responses were significantly reduced or undetectable in all LuTx patients compared to noTx patients. CONCLUSION: Patients in the early phase following lung allograft transplantation are vulnerable to infection with SARS-CoV-2 due to impaired immune responses. This patient population should be vaccinated before LuTx, protected from infection post-LuTx, and in case of infection treated generously with currently available interventions.
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BACKGROUND: Pulmonary embolism (PE) is an important complication of Coronavirus disease 2019 (COVID-19). COVID-19 is associated with respiratory impairment and a pro-coagulative state, rendering PE more likely and difficult to recognize. Several decision algorithms relying on clinical features and D-dimer have been established. High prevalence of PE and elevated Ddimer in patients with COVID-19 might impair the performance of common decision algorithms. Here, we aimed to validate and compare five common decision algorithms implementing age adjusted Ddimer, the GENEVA, and Wells scores as well as the PEGeD- and YEARS-algorithms in patients hospitalized with COVID-19. METHODS: In this single center study, we included patients who were admitted to our tertiary care hospital in the COVID-19 Registry of the LMU Munich. We retrospectively selected patients who received a computed tomography pulmonary angiogram (CTPA) or pulmonary ventilation/perfusion scintigraphy (V/Q) for suspected PE. The performances of five commonly used diagnostic algorithms (age-adjusted D-dimer, GENEVA score, PEGeD-algorithm, Wells score, and YEARS-algorithm) were compared. RESULTS: We identified 413 patients with suspected PE who received a CTPA or V/Q confirming 62 PEs (15%). Among them, 358 patients with 48 PEs (13%) could be evaluated for performance of all algorithms. Patients with PE were older and their overall outcome was worse compared to patients without PE. Of the above five diagnostic algorithms, the PEGeD- and YEARS-algorithms performed best, reducing diagnostic imaging by 14% and 15% respectively with a sensitivity of 95.7% and 95.6%. The GENEVA score was able to reduce CTPA or V/Q by 32.2% but suffered from a low sensitivity (78.6%). Age-adjusted D-dimer and Wells score could not significantly reduce diagnostic imaging. CONCLUSION: The PEGeD- and YEARS-algorithms outperformed other tested decision algorithms and worked well in patients admitted with COVID-19. These findings need independent validation in a prospective study.
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Background: The impact of devices for vessel closure on the safety and efficacy of cannula removal in VA-ECMO patients is unknown. Methods: We retrospectively analyzed 180 consecutive patients weaned from VA-ECMO after cardiac arrest or cardiogenic shock from January 2012 to June 2020. In the first period (historical technique group), from January 2012 to December 2018, primary decannulation strategy was manual compression. In the second period (current technique group), from January 2019 to June 2020, decannulation was performed either by a conventional approach with manual compression or by a suture-mediated closure device technique. Results: A femoral compression system was necessary in 71% of patients in the historical group compared to 39% in the current technique group (p < 0.01). Vascular surgery was performed in 12% in the historical cohort and 2% in the current technique cohort, which indicated a clear trend, albeit it did not reach significance (p = 0.07). Conclusion: We illustrated that a suture-mediated closure device technique for VA-ECMO decannulation was feasible, safe, and may have reduced the need of surgical interventions compared to manual compression alone.
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Oxigenação por Membrana Extracorpórea , Oxigenação por Membrana Extracorpórea/métodos , Artéria Femoral/cirurgia , Humanos , Estudos Retrospectivos , Técnicas de Sutura , SuturasRESUMO
PURPOSE: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2-40.2 versus median 11.9 mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7-3918 versus median 140 ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.
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COVID-19 , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Sistema Urinário , COVID-19/diagnóstico , Humanos , Masculino , RNA Viral , SARS-CoV-2/genética , Sistema Urinário/química , Eliminação de Partículas ViraisRESUMO
PURPOSE: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization. METHODS: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16). RESULTS: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface. CONCLUSION: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.
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COVID-19 , Escore de Alerta Precoce , Área Sob a Curva , COVID-19/diagnóstico , Humanos , Aprendizado de Máquina , Estudos Retrospectivos , SARS-CoV-2RESUMO
While previous reports showed ADP-induced platelet reactivity to be an independent predictor of bleeding after PCI in stable patients, this has never been investigated in patients with cardiogenic shock. The association of bleeding events with respect to ADP-induced platelet aggregation was investigated in patients undergoing primary PCI for acute myocardial infarction complicated by cardiogenic shock and with available on-treatment ADP-induced platelet aggregation measurements. Out of 233 patients, 74 suffered from a severe BARC3 or higher bleed. ADP-induced platelet aggregation was significantly lower in patients with BARC≥3 bleedings (p < .001). Multivariate analysis identified on-treatment ADP-induced platelet aggregation as an independent risk factor for bleeding (HR = 0.968 per AU). An optimal cutoff value of <12 AU for ADP-induced platelet aggregation to predict BARC≥3 bleedings was identified via ROC analysis. Moreover, the use of VA-ECMO (HR 1.972) or coaxial left ventricular pump (HR 2.593), first lactate (HR 1.093 per mmol/l) and thrombocyte count (HR 0.994 per G/l) were independent predictors of BARC≥3 bleedings. In conclusion, lower on-treatment ADP-induced platelet aggregation was independently associated with severe bleeding events in patients with AMI-CS. The value of platelet function testing for bleeding risk prediction and guidance of anti-thrombotic treatment in cardiogenic shock warrants further investigation.
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Difosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Hemorragia/etiologia , Infarto do Miocárdio/complicações , Choque Cardiogênico/etiologia , Doença Aguda , Idoso , Feminino , Hemorragia/fisiopatologia , Humanos , Masculino , Infarto do Miocárdio/patologia , Choque Cardiogênico/fisiopatologiaRESUMO
OBJECTIVE: Liver injury has frequently been reported in COVID-19 patients. The clinical relevance of liver injury related to SARS-CoV-2 infection remains unclear with a need for prospective studies on the impact of liver function test (LFT) abnormalities at baseline. DESIGN: Data of 217 patients without pre-existing liver disease prospectively included in the COVID-19 registry of the LMU university hospital were analysed in order to assess the association of abnormal LFT at admission and course of the disease. Severe course was defined as admission to the intensive care unit (ICU) or as COVID-19-related death. RESULTS: Abnormal LFT at baseline was present in 58% of patients, with a predominant elevation of aspartate aminotransferase (AST) (42%), gamma-glutamyltransferase (GGT) (37%) and alanine aminotransferase (ALT) (27%), hypoalbuminaemia was observed in 33%. Elevation of ALT and GGT, as well as hypoalbuminaemia, was associated with higher proportions of patients requiring ICU treatment and mechanical ventilation. After adjusting for age, gender and comorbidities, hypoalbuminaemia combined with abnormal AST or GGT at hospital admission was a highly significant independent risk factor for ICU admission (OR 46.22 and 38.8, respectively) and for a composite endpoint of ICU admission and/or COVID-19-related death (OR 42.0 and 26.9, respectively). CONCLUSION: Abnormal LFTs at hospital admission, in particular GGT and albumin, are associated with a severe course of SARS-CoV-2 infection.
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Biomarcadores/sangue , COVID-19/complicações , Hepatopatias/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Feminino , Hospitalização , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , gama-Glutamiltransferase/sangueRESUMO
BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.
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Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/etiologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/citologia , Plaquetas/metabolismo , Plaquetas/patologia , COVID-19 , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Humanos , Rim/patologia , Pulmão/patologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pandemias , Fenótipo , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Insuficiência Respiratória/diagnóstico , SARS-CoV-2 , Índice de Gravidade de Doença , Trombose/complicações , Trombose/diagnósticoRESUMO
A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimised care and early therapeutic interventions. We investigated the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding relative to disease severity.We analysed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardised nasopharyngeal swab or sputum samples were collected. If patients were mechanically ventilated, endotracheal aspirate samples were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 out of 92) of COVID-19 patients had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between nonsevere and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time-course of C-reactive protein, interleukin-6 and procalcitonin revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17â days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and nonsevere COVID-19 cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between the second and third week, and prolonged viral shedding are associated with a more severe disease course.
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COVID-19 , SARS-CoV-2 , Humanos , RNA Viral , Sistema Respiratório , Índice de Gravidade de Doença , Eliminação de Partículas ViraisRESUMO
PURPOSE: SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. METHODS: We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. RESULTS: A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). CONCLUSION: In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. TRIAL REGISTRATION: COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.
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COVID-19/fisiopatologia , Disfunção Ventricular/fisiopatologia , Idoso , COVID-19/complicações , COVID-19/diagnóstico por imagem , COVID-19/patologia , Ecocardiografia Tridimensional , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2 , Volume Sistólico , Troponina T/sangue , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/etiologia , Disfunção Ventricular/patologiaRESUMO
BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.
Assuntos
COVID-19 , Infecção Hospitalar , Infecção Hospitalar/epidemiologia , Genoma Viral , Genômica , Alemanha/epidemiologia , Hospitais , Humanos , Filogenia , SARS-CoV-2RESUMO
Cardiogenic shock is still a major driver of mortality on intensive care units and complicates â¼10% of acute coronary syndromes with contemporary mortality rates up to 50%. In the meantime, percutaneous circulatory support devices, in particular venoarterial extracorporeal membrane oxygenation (VA-ECMO), have emerged as an established salvage intervention for patients in cardiogenic shock. Venoarterial extracorporeal membrane oxygenation provides temporary circulatory support until other treatments are effective and enables recovery or serves as a bridge to ventricular assist devices, heart transplantation, or decision-making. In this critical care perspective, we provide a concise overview of VA-ECMO utilization in cardiogenic shock, considering rationale, critical care management, as well as weaning aspects. We supplement previous literature by focusing on therapeutic issues related to the vicious circle of retrograde aortic VA-ECMO flow, increased left ventricular (LV) afterload, insufficient LV unloading, and severe pulmonary congestion limiting prognosis in a relevant proportion of patients receiving VA-ECMO treatment. We will outline different modifications in percutaneous mechanical circulatory support to meet this challenge. Besides a strategy of running ECMO at lowest possible flow rates, novel therapeutic options including the combination of VA-ECMO with percutaneous microaxial pumps or implementation of a venoarteriovenous-ECMO configuration based on an additional venous cannula supplying towards pulmonary circulation are most promising among LV unloading and venting strategies. The latter may even combine the advantages of venovenous and venoarterial ECMO therapy, providing potent respiratory and circulatory support at the same time. However, whether VA-ECMO can reduce mortality has to be evaluated in the urgently needed, ongoing prospective randomized studies EURO-SHOCK (NCT03813134), ANCHOR (NCT04184635), and ECLS-SHOCK (NCT03637205). These studies will provide the opportunity to investigate indication, mode, and effect of LV unloading in dedicated sub-analyses. In future, the Heart Teams should aim at conducting a dedicated randomized trial comparing VA-ECMO support with vs. without LV unloading strategies in patients with cardiogenic shock.
Assuntos
Oxigenação por Membrana Extracorpórea , Coração Auxiliar , Humanos , Estudos Prospectivos , Circulação Pulmonar , Choque Cardiogênico/terapiaRESUMO
PURPOSE: It has been established that the infection with SARS-CoV-2 may cause an impairment of chemosensory function. However, there is little data on the long-term effects of SARS-CoV-2 infection on chemosensory function. METHODS: Twenty three SARS-CoV-2-positive patients diagnosed in spring 2020 with subjective hyposmia (out of 57 positive patients, 40.3%) were compared to SARS-CoV-2-positive patients without hyposmia (n = 19) and SARS-CoV-2-negative patients (n = 14). Chemosensory function was assessed by the Brief Smell Identification Test (BSIT), Taste Strips (TS), Visual Analogue Scales (VAS), and the SNOT-22. The initial cohort with hyposmia were also examined at 8 weeks and 6 months after initial examination. RESULTS: There were no differences between the SARS-CoV-2-positive cohort without hyposmia and negative controls in terms of BSIT (8.5 ± 2.6 vs. 10.2 ± 1.8), TS (3.4 ± 0.6 vs. 3.9 ± 0.3) or VAS (2.1 ± 1.3 vs. 1.1 ± 0.5); yet the SNOT-22 was significantly elevated (27.7 ± 11.2 vs. 16.4 ± 10.8). The SARS-CoV-2-positive group with hyposmia performed significantly poorer in BSIT (4.0 ± 1.7 vs. 8.5 ± 2.6/10.2 ± 1.8), TS (2.6 ± 1.3 vs. 3.4 ± 0.6/3.9 ± 0.3), and VAS (7.9 ± 2.2 vs. 2.1 ± 1.3/1.1 ± 0.5) compared to both control groups. At week 8 and month 6 control, six and five patients, respectively, still suffered from subjectively and objectively impaired chemosensory function. The other patients had recovered in both respects. CONCLUSION: SARS-CoV-2 patients with subjectively impaired chemosensory function regularly perform poorly in objective measurements. About 70% of patients suffering from olfactory dysfunction in SARS-CoV-2 quickly recover-the rest still suffers from considerable impairment 6 months after infection.
Assuntos
COVID-19 , Transtornos do Olfato , Seguimentos , Humanos , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/etiologia , SARS-CoV-2 , Olfato , Distúrbios do PaladarRESUMO
Objective: Acute cardiogenic shock is a life-threatening condition with mortality rates of up to 50%. If conventional therapy fails, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy has emerged to a promising alternative for temporary cardiac and respiratory support in specialized centers. However, it is only a bridge to recovery, final decision, heart transplantation or the permanent implantation of a left ventricular assist device. Therefore, the identification of the optimum weaning time point is challenging, and standardized weaning protocols are rare. Methods: In this explorative pilot study, we evaluated the potential benefit of blood flow measurements in the aortic arch using an ultrasonic cardiac output monitor (USCOM) for the primary endpoint of successful VA-ECMO weaning. 12 patients under VA-ECMO therapy for acute cardiogenic shock and a hemodynamic condition which qualified for a stepwise weaning process were included in this study. Main exclusion criterion was the presence of additional venting therapy for left ventricular unloading, e.g. Impella. Statistical comparisons were performed using the Mann-Whitney test and corrected for multiple testing by the Holm-Sidak method. Results: Peak velocity of flow in the aortic arch showed a positive correlation with weaning success independent of ECMO flow (weaning success vs. failure: 0.75 vs. 0.35 m/s (low ECMO support), p = 0.049), whereas we identified only a trend for mean pressure gradient, minute distance and stroke volume index. Conclusion: We hypothesize, that USCOM might provide an additive benefit to conventional strategies in its ability to predict successful VA-ECMO weaning and prevent pulmonary congestion. Larger upcoming trials are required to address this relevant topic and provide standardized treatment protocols for optimized weaning in the future.